delta8(9)-steroids and their process of preparation



ilnited S ates Patent A STERQIDS AND THEIR PROCESS OF PREPARATION .loset Fried, New Brunswick, N. J., assignor to Olin Mathieson Chemical Corporation, New York, N. 1., a corporation of Virginia No Drawing. Application July 7, 1954 Serial No. 441,932

13 Claims. (Cl. 26fi -397.3)

The n -ll-lceto steroids of the pregnane series are new compounds which have adrenocortical activity.

The steroids useful as starting materials in the practice of this invention are disclosed in J. Am. Chem. Soc. 75, 2273 (1953), and also in my U. S. application Serial No. 417,489, filed March 10, 1954, and are represented by the following general formula:

wherein the 4,5 position is double-bonded or saturated (the 4,5-double-bonded steroids being preferred), and wherein R is hydrogen, R is hydroxy, or together R and R is x0 (keto) or a group convertible thereto by bydrolysis (e. g. acetal), R and R as oxo being preferred; Z is hydrogen or tx-hydroxy; X is halo (preferably bran-1o); and Y is hydrogen, halogen, hydroxy, or OR", where R is an acyl radical or a hydrocarbon radical, the former being exemplified by a carboxy radical such as lower alkanoyl (e. g. acetyl propionyl, and butyryl) and aroyl (e. g. benzoyl and naphthoyl), and the latter by lower alkyl (e. g. methyl, ethyl, and propyl) and aralkyl (e. g. benzyl and phenethyl).

These starting materials are reacted in accordance with the process of this invention to produce the new steroids represented by the following general formula CHzY wherein the 4,5-position is double-bonded or saturated (the 4,5-double-bonded steroids being preferred), and

wherein R, R Z and Y are as above-defined. When Y is R"O, the compounds can be hydrolyzed by means of "ice dilute base or acid to form the corresponding free 21- hydroxy derivatives.

Compounds suitable as initial reactants in the process of this invention include, inter alia, 9ot-bromo-cortisone ZI-acetate (or other carboxylic acid ester), t-bI'OmO-11- keto-progesterone, 9a-bromo-11-keto ZI-hydroxyprogesterone 21-acetate (or other carboxylic acid ester); 9abromo-ll-keto-l7a-hydroxy-progesterone; and the corresponding 9a-chloro, fluoro and iodo compounds.

The steroids formed by the practice of this'invention include, inter alia, A -dehydrocortisone 2l-acetate (or other carboxylic acid esters), A -pregnadiene-3,l1,20- trione; 1l-keto-21.-hydroxy-A -dehydroprogesterone 21- acetate (or other carboxylic acid ester); and ll-keto-l7ahydroxy-M -dehydroprogesterone.

The h -steroids of the pregnane series are formed from the corresponding 9a-halo-steroids by heating the latter, preferably to reflux, in the presense of a nitrogenous base, such as a lower-alkyl substituted pyridine (e. g., picoline, lutidine, collidine, etc. A collidine is particularly preferred. The resulting A -steroid is then separated by extraction and evaporation of the extracting agent.

The following examples are illustrative of the invention (all temperatures being in centigrade):

EXAMPLE 1 A -dehydr0cortis0ne acetate CHQO O C CH;

A suspension of 102 mg. A -9u-brom0pregnene-l7m, 21-diol-3,11,20-trione 21-acetate in /2 ml. of freshly distilled collidine is refluxed for ten minutes. The resulting mixture is diluted with chloroform and extracted with dilute sulfuric acid, Water, sodium bicarbonate and again with water. The chloroform extract on evaporation to dryness in vacuo leaves about 76.7 mg. of a crystalline residue which is recrystallized from ethanol with the aid of Darco. The pure A -dehydrocortisone acetate melts at 248-249 C. with browning, and has [a] +412 (c., 0.67 in chloroform);

M31; 235 m (e=l7,200); m3? 2.96,:i, 5.72 5.88 1, 6.06 1, 6.26 6.35;.t

Analysis.-Calcd. for C H O C, 68.98; H, 7.05. Found: C, 68.81; H, 7.28.

This substance possesses about 0.4 times the activity of cortisone acetate in the rat liver glycogen assay.

A -dehydrocortisone acetate may be hydrolyzed with sodium methylate in methanol to form A -dehydrocortisone.

EXAMPLE 2 A -pregnadiene-21 -0l-3,11 ,2 O-trione 21 -acetate [ILkelo-ZI-acetoxy-M dehydroprogesterone] CHrO O OOH! A solution of 31 mg. of 9a-bromo-1l-dehydrocorti- -costerone acetate in 0.25 ml. of freshly distilled s-collidine is refluxed for 10 minutes. The reaction mixture is diluted with chloroform and the resulting solution extracted with dilute sulfuric acid. The extract is washed with water, sodium bicarbonate and again with water and dried over sodium sulfate. Evaporation in vacuo leaves a residue (about 29.2 mg.) which is dissolved in 2 m1.

of benzene and 0.5 ml. of hexane and chromatographed on 600 mg. of sulfuric acid-washed alumina. Elution of the column with benzene (200 ml.) and with benzenechloroform 3:1 affords essentially pure n -pregnadiene-2l-ol-3,11,20-trione 2l-acetate. After two recrystallizations from acetone-hexane the material melts at 149150 C.; [M +408 (e., 0.55 in chloroform);

hfifl' 235 mp. (6 18.500), shoulder at 245 mp (e=17,300)

Analysis.--Calcd. for C H O (384.45): C, 71.85; H, 7.34. Found: C, 71.88; H, 7.23.

A -pregnadiene-21-ol-3,l1,20-trione Zl-acetate may be hydrolyzed by treatment with sodium methylate to form A -pregnadiene-21-ol-3,11,20-trione.

EXAMPLE 3 11-ket0A -dehydrpr0gester0ne [A -pregnadiene- 3,11,20-trione] 30.5 mg. of 9a-bromo-1l-ketoprogesterone is treated with 0.25 ml. of collidine as described in Example 1. The resulting crude product (about 26.2 mg); is taken up in 2 ml. of benzene and 0.5 ml. of hexane and chromatographed on 500 mg. of sulfuric acid-washed alumina. Elution of the column with benzene-hexane 4:1 and eventually with benzene yields crude A -dehydro-ll ketoprogesterone, which after 3 recrystallizations from acetone-hexane melts at 193-194 C.; [a] +54l (c., 0.27 in chloroform);

A315; 235 mu (e=21,100), shoulder at, 248 mu =18,200)

Analysis.-Calcd. for C E- 0 (326.42): C, 77.27; H, 8.03. Found: C, 77.26; H, 7.88.

In a similar manner, 9ot-bromo-1l-keto-l7ot-hydroxyprogesterone can be converted to ll-keto-lh-hydroxy- A -dehydroprogesterone.

The invention may be otherwise embodied within the scope of the appended claims.

I claim:

1. The process for dehydrohalogenating a 9a-halo-1lketo steroid of the pregnane series which comprises heating said steroid in the presence of a lower-alkyl substituted pyridine, and recovering the steroid formed.

2. The process of claim 1 wherein the pyridine is collidine.

3. The process for dehydrobrominating a 9a-bromoll-keto steroid of the pregnane series which comprises heating said steroid in the presence of a lower-alltyl substituted pyridine, and recovering the steroid formed.

4. The process for dehydrohalogenating a 904-112110- 3,l1,20-triketo-steroid of the A -pregnene series which comprises heating said steroid in the presence of a loweralkyl substituted pyridine, and recovering the steroid formed.

5. The process for producing A -dehydrocortisone acetate which comprises heating 9u-bromocortisone acetate in the presence of a lower-alkyl substituted pyridine, and recovering the A -dehydrocortisone acetate thus formed.

6. The process for producing A -pregnadiene-21 ol-3,11,20-trione 2l-acetate which comprises heating cbromo-ll-dehydrocortisone acetate in the presence of a lower-alkyl substituted pyridine, and recovering the A -pregnadiene-2l-ol-3,l1,20-trione thus formed.

7. The process for producing A -dehydro-l l-ketoprogesterone which comprises heating 9a-bromo-ll-ketoprogesterone in the presence of a lower-alkyl substituted pyridine and recovering the A -dehydr0-1l-ketoprogesterone thus formed.

8. A steroid of the general formula CHzY cglil wherein Z is a radical selected from the group consisting of hydrogen and hydroxy and Y is a radical selected from the group consisting of hydrogen, hydroxy, lower alkanoyloxy and aroyloxy.

9. A -3,ll,2O-triketo17-l1ydroxy-2l-acetoxy pregnadiene.

10. A -3,11,2O-triketo 17,21 dihydroxy pregnadiene.

11. A -pregnadiene-2l-ol-3,11,20-trione 21-acetate.

12. A -pregnadiene-21-ol-3,11,20-trione.

13. A -dehydro-1l-ketoprogesterone.

References Cited in the file of this patent UNITED STATES PATENTS 2,409,798 Reichstein Oct. 22, 1946 

13. $8(9)-DEHYDRO-11-KETOPROGESTERONE. 